The presence of particular neurotransmitter receptors in particular numbers on the surface of the postsynaptic membrane results from a complex interplay between many factors. In the case of hippocampal excitatory synapses, the particular number of AMPA receptors appears to be the main factor that controls synaptic strength, while their particular type appears to control the mechanisms by which the number of receptors can be changed. In the prior (and initial) 5 years of this grant, we established that hippocampal synaptic plasticity, namely long-term potentiation (LTP), depression (LTD) and its variations (e.g. depotentiation), behave in a state-dependent manner with respect to the ability to undergo plasticity. Understanding this state-dependence is important in at least two respects. First, it provides greater understanding of the large number of processes of the brain that are influenced by this plasticity. Second, understanding the rules of state-dependence informs as to the mechanisms that underlie synaptic plasticity. In this proposal, we seek to use the rule-map that an understanding of state-dependent plasticity provides to probe for the nature of these underlying mechanisms. To do so, we will continue to use the technique of recording from pairs of synaptically connected hippocampal neurons as a way of recording from the smallest possible populations of synapses, and which provides the experimental ability to control the pre-or postsynaptic environment of synapses in known synaptic states. Synaptic plastic processes such as LTP and LTD play a central role in virtually all models that seek to explain learning and memory at a cellular level. Beyond even that, LTP and LTD are found in many brain areas and have been proposed to play a role in a wide range of neural functions and disorders. Neural functions from fear and emotion, through memory to addiction have been proposed to have a basis in these plastic processes. Therefore, the understanding of the mechanisms that underlie this plasticity will provide wide-ranging benefits not only to understanding normal brain function, but also many neurological and mental disorders. PUBLIC HEALTH RELEVANCE: The processes of synaptic plasticity have traditionally been associated with learning and memory, but in fact underlie practically everything the brain does, and have been strongly implicated in a variety of physical and mental disorders, including, but certainly not limited to: Alzheimer's disease, Huntington's disease, autism, anxiety disorders, drug addiction, learning disabilities, and many more. Discovery of the underlying mechanisms of synaptic plasticity is so fundamental to understanding scores of mental disorders, that designing effective treatments and/or cures for these disorders without this knowledge would be akin to trying to learn quantum physics without first knowing the alphabet. The relevance of this proposed research to public health is that it will provide new knowledge key to designing treatments for many nervous and mental disorders, and thus, will greatly assist in the improvement of the public's mental health.